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An implementation of neural simulation-based inference for parameter estimation in ATLAS
No full textAbstract Neural simulation-based inference (NSBI) is a powerful class of machine-learning-based methods for statistical inference that naturally handles high-dimensional parameter estimation without the need to bin data into low-dimensional summary histograms. Such methods are promising for a range of measurements, including at the Large Hadron Collider, where no single observable may be optimal to scan over the entire theoretical phase space under consideration, or where binning data into histograms could result in a loss of sensitivity. This work develops a NSBI framework for statistical inference, using neural networks to estimate probability density ratios, which enables the application to a full-scale analysis. It incorporates a large number of systematic uncertainties, quantifies the uncertainty due to the finite number of events in training samples, develops a method to construct confidence intervals, and demonstrates a series of intermediate diagnostic checks that can be performed to validate the robustness of the method. As an example, the power and feasibility of the method are assessed on simulated data for a simplified version of an off-shell Higgs boson couplings measurement in the four-lepton final states. This approach represents an extension to the standard statistical methodology used by the experiments at the Large Hadron Collider, and can benefit many physics analyses
Histopathologically confirmed radiation necrosis: Risk factors and clinical outcomes in patients with primary brain tumors
No full textAbstract Background Radiation necrosis is a recognized complication following radiotherapy for primary brain tumors, presenting diagnostic and therapeutic challenges, and potentially masquerading as tumor recurrence. This study aims to delineate the clinical trajectory, management strategies, and outcomes of histologically confirmed radiation necrosis in patients treated for primary brain tumors. Methods We conducted a retrospective review of patients who underwent surgical intervention for suspected tumor recurrence at our institution between 2010 and 2022, following adjuvant radiotherapy. Cases with histopathologically confirmed radiation necrosis were identified and analyzed for onset, clinical symptoms, radiological features, correlation with radio- and chemotherapy, management approaches, and disease progression. Results Out of 276 patients operated for suspected recurrent brain tumors, 14 (5%) were histopathologically diagnosed with radiation necrosis. The latency period from radiotherapy to diagnosis ranged from 3 to 40 months. Notably, patients with oligodendrogliomas exhibited a significantly higher incidence of radiation necrosis (26%), underscoring a substantial risk association (P < 0.001). Conversely, the rates of radiation necrosis in patients with glioblastoma and astrocytoma (WHO grade II and III) were lower, at 2% and 0%, respectively, suggesting a lower risk association (P < 0.001 and P = 0.036, respectively). The majority (79%) of these patients were asymptomatic and exhibited a favorable clinical course, with most cases showing no progression of necrosis. During the follow-up period, tumor recurrence was verified in 2 patients. Conclusion Radiation necrosis post-radiotherapy for primary brain tumors occurs infrequently but predominantly in patients with oligodendrogliomas, often following a benign course. The study underscores the importance of close monitoring for this condition, given the potential for sampling errors and the critical need for histopathological confirmation to guide appropriate management
Sharp Page transitions in generic Hamiltonian dynamics
No full textNational Science Foundation http://dx.doi.org/10.13039/100000001Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Kavli Institute for Theoretical Physics, University of California, Santa Barbara http://dx.doi.org/10.13039/10000595
The use of plant, bacterial and fungal resources in soil food webs of ecto‐ and arbuscular mycorrhiza‐dominated deciduous forests
No full textAbstract Soil food webs, driven by complex interactions among plants, microbes and invertebrates, are crucial for carbon and nutrient cycling in forest ecosystems. Over the last decade, it has become evident that forests dominated by arbuscular mycorrhizal fungi (AMF) or ectomycorrhizal fungi (EMF) differ in their litter chemistry and microbial community composition, leading to different carbon and nutrient cycling. Still, the role of soil invertebrates in soil food webs of AMF‐ and EMF‐dominated forests remains undescribed. Here, we tested whether trophic positions (TP) and basal resources of nine soil invertebrate groups (Araneae, Chilopoda, Collembola, Diplopoda, Diptera, Isopoda, Lumbricina, Mesostigmata and Oribatida) are different in AMF‐ (maple and/or ash) and EMF‐dominated (beech and/or oak) deciduous forests. We addressed this question using compound‐specific stable isotope analysis of carbon and nitrogen in amino acids (CSIA‐AA)—a novel method that allows precise estimation of the TP and basal resource use (bacteria, fungi and plant) of consumers in field conditions. Plant‐ and microbial‐derived resources of soil invertebrates generally varied little between AMF‐ and EMF‐dominated forests. We only found a slight tendency of soil invertebrates in AMF‐dominated forests relying more on fungal‐derived resources (ca. 2% difference) and more on bacteria‐derived resources in EMF‐dominated systems (ca. 2% difference). Most of the variation in resource use was explained by the taxonomic identity of invertebrates, independently of the forest type and location. Mesofauna, particularly Collembola and Oribatida, were key consumers of fungi (relative contribution 49%–72.1%), while macrofauna (except earthworms) relied more on plant resources (relative contribution 42.1%–58.9%), suggesting that different size compartments of soil food webs predominantly use different basal resources. Earthworms and Myriapoda (Chilopoda and Diplopoda) had the highest proportions of bacteria‐derived essential amino acids (relative contribution 23.2%–35.2%). TPs of taxa remained largely consistent across mycorrhizal types (except for an elevated TP of Isopoda in EMF‐dominated forests), suggesting similar vertical organization of soil food webs across the studied forests. Overall, our study shows that TPs and basal resource use of soil fauna vary little across temperate deciduous forests, being mainly explained by the faunal taxonomic identity. Read the free Plain Language Summary for this article on the Journal blog.Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165
Small net local temporal changes in taxonomic, functional, and phylogenetic biodiversity across European temperate forests
No full textSummary We face increasing concerns about how the local diversity of native plant communities responds to various drivers of global change, yet often lack comprehensive studies that integrate several components of diversity and the effects of both local and regional drivers of change. We analyzed changes in taxonomic, functional, and phylogenetic diversity across 2681 (semi‐)permanent temperate forest understory plots surveyed and resurveyed for all vascular plants over intervals of 15–78 yr, spanning 72 regions distributed across Europe. We quantified temporal changes in these diversity indices and assessed their responses to changes in both local drivers (plot‐level overstory cover, indicator values for soil nutrients) and regional shifts in macroclimate and nitrogen deposition. Overall, local changes in taxonomic, functional, and phylogenetic diversity were centered around zero, reflecting – on average – little net change in forest diversity. Observed diversity changes mostly reflected local conditions such as overstory cover change and baseline soil nutrients rather than regional drivers of large‐scale change. Changes in phylogenetic diversity correlated positively with changes in taxonomic diversity but negatively with changes in functional diversity. Our findings underscore the importance of local habitat management and multifaceted diversity monitoring for effective biodiversity conservation in temperate forests.Deutsches Zentrum für integrative Biodiversitätsforschung Halle-Jena-Leipzig https://doi.org/10.13039/501100020056Agentúra na Podporu Výskumu a Vývoja https://doi.org/10.13039/501100005357European Agricultural Fund for Rural Development https://doi.org/10.13039/501100014141Centre de Coopération Internationale en Recherche Agronomique pour le Développement https://doi.org/10.13039/501100007204Akademie Věd České Republiky https://doi.org/10.13039/50110000424
Higher Moments and Efficiency Gains in Recursive Structural Vector Autoregressions
No full textABSTRACT Recursive SVAR models are identified by covariance conditions derived from the assumption of uncorrelated shocks. Recent literature has advocated using additional higher‐order moment conditions implied by independent shocks. This paper characterizes the redundancy properties of these higher‐order coskewness and cokurtosis conditions by showing that recursive SVAR estimators that rely exclusively on covariance conditions, neglecting the additional identifying information in higher‐order moments, are asymptotically inefficient. Moreover, we prove that some higher‐order moment conditions are always redundant and provide no improvement in asymptotic efficiency. A simulation demonstrates that excluding redundant conditions is essential to achieve performance gains in small samples.Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165
Immunophenotyping of Patients With Rheumatoid Arthritis Reveals Difference in CD27 + IgD + Unswitched Memory B Cell Profiles
No full textObjectives: Over the past decades, the prevalence of noncommunicable diseases has surged significantly, including the systemic autoimmune disorder rheumatoid arthritis (RA). Despite extensive research and advancement of RA therapy, effective prevention strategies or cures remain elusive, and the mechanisms underlying RA pathogenesis unclear. It is crucial to gain deeper insights into RA pathophysiology. The objective of this study is to provide a comprehensive immunophenotyping of patients with RA. Methods: We generated and analyzed deep immunophenotyping data from 52 patients with RA and 47 healthy controls (HCs). Whole blood samples were stained with extracellular markers, and intracellular antibodies and analyzed for 32 different cell markers using mass cytometry by time of flight. The acquired data was analyzed by both manual and automatic unsupervised tools and subsequently complemented with anthropometric data and clinical‐laboratory parameters. Results: We observed a significant disparity in immune cell profiles between patients with RA and HC, notably a reduced frequency of CD27 + IgD + unswitched memory B ( m B) cells in patients with RA ( p ‐value < 0.01), with the disease RA being the primary and only significant factor explaining up to 17.9% of the variance of these cells. Conclusion: Our results reveal, for the first time, that a reduced frequency of unswitched m B cells in patients with RA is the only significant abnormality distinguishing patients with RA from HC in a complex immunophenotyping panel of 72 different cell populations. This provides important information to further individualize various interventions and possibly help to design novel therapeutic interventions.European Research Council https://doi.org/10.13039/50110000078
Physiotherapeutic management of patients with SMA: A questionnaire-based online survey among physiotherapists within the SMArtCARE network
No full textBackground and objectives: Disease-modifying treatments (DMT) have dramatically changed phenotypes in patients with spinal muscular atrophy (SMA). Because publications regarding standards of care were published before DMTs emerged, detailed recommendations and guidelines for physiotherapeutic management are still lacking. The objective of this study was to map the physiotherapeutic management of patients with SMA within the SMArtCARE network, a disease-specific registry for patients with 5q-SMA with 83 participating centers in Germany, Switzerland, and Austria. Methods: An online survey using a modified Delphi approach was conducted among physiotherapists with two questionnaire rounds between June 2022 and June 2023. Seven physiotherapeutic experts developed and revised the questionnaires focusing on the main topics of stretching, positioning, mobility and exercise, and chest physiotherapy. The second questionnaire was based on eight different case studies. Results: The second questionnaire was sent to 148 participants with a response rate of 28%. Most of the physiotherapists were well experienced in treating SMA patients. There was a strong consensus that home-based stretching should be used in pediatric patients with contractures regardless of their motor function. Muscle strengthening training was considered to be essential for all sitters and for walkers with moderate motor function restriction by a strong consensus. For all patients with respiratory involvement there was a consensus for prophylactic respiratory therapy. Conclusion: Our results describe the current physiotherapeutic management and recommendations within the SMArtCARE network. These findings highlight the need for an individualized approach, and the necessity of developing and adjusting existing guidelines
Discovery of molecularly-informed therapeutic strategies for mature T-cell leukemias and lymphomas
No full textMature T-cell leukemias and lymphomas (mTCL) comprise a clinically and genetically heterogeneous group of lymphoid malignancies. Most subtypes of peripheral T-cell lymphomas and leukemic T-cell malignancies show an aggressive clinical course and poor prognosis. Thus, these diseases urgently require novel therapeutic strategies. Taking advantage of recent progress deciphering the genetic basis of mTCL, we generated a comprehensive database of genetic alterations from 1 825 patients with mTCL and utilized bioinformatic methodology developed to support treatment decisions in molecular tumorboards to identify novel potential therapeutics. Based on the results of this approach, we performed a systematic in vitro drug screen in molecularly characterized cell lines of mTCL to assess the activity of potential therapeutics. Of these, the cell cycle regulator WEE1 stood out as a novel therapeutic target in a genetically defined subgroup of mTCL. Indeed, WEE1 kinase inhibitors potently induced replication stress, premature mitotic entry, accumulation of DNA damage and induction of apoptosis in mTCL cell lines. Building on the single-agent activity of clinical grade WEE1 inhibitors, we next explored potential drug combination strategies through mechanistic studies. With this, we identified strong synergistic effects of combined WEE1 and JAK inhibition in genetically defined subtypes of mTCL, including primary patient samples of T-cell prolymphocytic leukemia. In summary, our study provides a comprehensive overview of the genetic landscape in mTCL and potential therapeutics in genetically defined subtypes. As such, we identified synergistic effects of dual WEE1 and JAK inhibition in cases with altered JAK/STAT signaling as a blueprint for clinical testing
Neurodegeneration in Parkinson’s disease: are we looking at the right spot?
No full textAbstract Parkinson’s disease (PD) is recognized as the fastest-growing neurodegenerative disorder, impacting millions of individuals worldwide. It is primarily characterized by cardinal motor symptoms, including bradykinesia (slowness of movement), tremor, rigidity, and postural instability, which significantly impair the quality of life of those affected. Traditionally, the prevailing hypothesis has attributed these motor symptoms to the degeneration and subsequent loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Currently, emerging research suggests that this neuron-centric view may be overly simplistic and not entirely accurate. In light of this, growing attention has turned to the role of axons within the nigrostriatal pathway—an extensive network connecting the substantia nigra to the striatum, essential for both dopamine transmission and the overall functioning of the motor control by the brain. By directing a focus toward this aspect, in this nano review article we examine why nigrostriatal axons deserve increased attention and should be considered a pivotal target for further therapeutic strategies in PD.National Council for Scientific and Technological Development http://dx.doi.org/10.13039/501100003593Coordination of Superior Level Staff Improvemen